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Discovery of UHRF1 inhibitors in the treatment of hepatocellular carcinoma

UHRF1抑制剂治疗肝细胞癌的发现

基本信息

批准号：
9635376
负责人：
Damian Winston Young
金额：
$ 10.03万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9635376
关键词：
Address Affect African American Antineoplastic Agents Apoptosis BAY 54-9085 Binding Biological Biological Assay Cancer cell line Catalytic Domain Caucasians Cell Proliferation Cells Chemicals Chemistry Chromosomal Instability DNA DNA Methylation DNA Modification Methylases Development Diagnosis Disease Education Epigenetic Process Evaluation FDA approved Fingers Gene Expression Genes Genetic Genomics Goals Hepatocyte Hispanics Human Incidence Individual Latino Ligands Luciferases Malignant Epithelial Cell Malignant Neoplasms Medical Methods Methylation Neoplasm Metastasis Oncogene Activation Operative Surgical Procedures Outcome PHD Finger Pathway interactions Patients Peptoids Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacology Study Pilot Projects Plants Population Primary carcinoma of the liver cells Property Proteins Regulation Reporter Retrotransposon Ring Finger Domain Sampling Technology Testing Therapeutic Treatment Efficacy Tumor Suppressor Genes Ubiquitin Ubiquitination Underrepresented Populations United States Western Blotting base cancer cell cytotoxicity daughter cell derepression drug discovery effective therapy genome wide methylation hepatocellular carcinoma cell line high risk high throughput screening homeodomain improved inhibitor/antagonist innovation kinase inhibitor liver transplantation methylome negative affect neoplastic cell new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics outcome forecast overexpression prognostic programs protein protein interaction recruit screening small molecule success tumor tumor progression ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY (PILOT PROJECT 1) The overarching goal of this collaborative pilot proposal is the development of a novel approach to treat hepatocellular carcinoma (HCC)—a cancer affecting underrepresented populations in the US at a higher rate. One of the signatures of HCC is the manifestation of global levels of DNA hypomethylation which contributes to tumor progression and metastasis. Although epigenetic therapeutic approaches are on the rise, there are currently no drugs that mechanistically function to reduce DNA hypomethylation. Toward the goal of treating UR populations that are significantly impacted by HCC, we will develop compounds that reduce DNA hypomethylation through a novel therapeutic target. Ubiquitin-like with plant and homeodomain (PHD) and really interesting new gene (RING) finger domains 1 (UHRF1) is a master regulator of the DNA methylome. Overexpression of UHRF1 drives DNA hypomethylation in HCC and tumor progression. UHRF1 is an E3 ligase that affects the negative regulation of the de novo DNA methyltransferase DNMT3A through ubiquitination and degradation. Loss of DNMT3A, in turn, leads to global hypomethylation in cancers. Therefore, as a means toward reducing global hypomethylation in HCC, the focus of this pilot project is the development small- molecules or peptoids that inhibit the UHRF1-DNMT3A protein-protein interaction (PPI). Compounds that inhibit this interaction will rescue DNMT3A levels in HCC cells leading to decreases in genomic hypomethylation and the mitigation of HCC proliferation. To identify compounds that function as UHRF1- DNMT3A inhibitors, we propose in Specific Aim 1 to deploy two discovery platforms in a parallel fashion: DNA- Encoded Chemistry Technology (DEC-Tec) and on-bead peptoid screening. Each of these platforms provides an economical access to a large chemical space that will likely be needed to identify compounds capable of disrupting the UHRF1-DNMT3A interaction. Under the aegis of Specific Aim 2, we will evaluate the biological effects of the UHRF1-DNMT3A inhibitors by executing a suite of biological assays on cancer cell lines generated from HCC tumors obtained from African American and Hispanic/Latino patients. These highly useful cancer cell lines will allow us to develop our compounds within the genetic backgrounds of populations most susceptible to HCC. We will determine the effects of hypomethylation reducing compounds on cellular DNA methylation levels, gene expression, and cancer cell proliferation and apoptosis. Medicinal chemistry will be performed to improve compound potency and biological efficacy leading to approximately six final compounds for which we will conduct preliminary pharmacological studies. The successful completion of this project will afford a novel therapeutic mechanism for the treatment of HCC and have particularly salutary relevance within greatly affected UR populations.

项目总结（试点项目一）